Cell cycle regulation in oocytes: can we prevent chromosome division errors that result in infertility and miscarriage?

Background. Accurate cell division relies on the alignment of all chromosomes so that they segregate equally into two new daughter cells. Unfortunately, mammalian oocytes often divide before their chromosomes are properly aligned, producing an egg with an abnormal number of chromosomes. In humans this is the number one genetic reason for failed pregnancy, miscarriage and developmental disabilities in babies.

When compared to other types of cell division, we know relatively little about cell cycle regulation in mammalian oocytes. Therefore, understanding why some oocytes fail and others progress is of critical importance to the 70,000+ UK patients undergoing IVF each year.

Objectives and Experimental Approach. On average, it takes 6 cycles of IVF to have a greater chance of having a baby than not. The objective of this project is to understand correct cell cycle regulation in oocyte cell division and, to use this information to identify cell cycle protein markers of either competent or incompetent oocytes.

Using the oocytes of younger and older mice (excellent models of lower and higher frequency chromosome division errors), the student will monitor the temporospacial regulation of ~30 key proteins involved in cell division by a single cell technology known as imaging mass cytometry (IMC). Following this, he/she will use live oocytes to fully characterise proteins that differ, using techniques such as fluorescent protein expression, protein knock down and confocal microscopy. Finally, there will be an opportunity to manipulate key protein levels, aiming to 'rescue' oocytes that would otherwise be at risk of committing division errors.

Novelty and Timeliness. This studentship project is both highly novel and timely, its take advantage of a major advance in the field (my own publication earlier this year) and a cutting edge technologies to address a global problem of increasing impact. 15% of couples currently suffer infertility and the yearly UK spend on IVF is >£350,000,000.

Previously, two major factors have limited cell division studies in oocytes. Firstly, a lack of evidence demonstrating how different cell cycle regulation is in mammalian oocytes, and secondly, the difficult nature of the material. However, my recently published (and unpublished) Wellcome Fellowship research changes the current dogma with regard to cell cycle regulation in oocytes and, the rapid evolution of IMC will now allow an unprecedented levels of information to be gained from each single oocyte. Importantly, I have preliminary data demonstrating the application of this technology for the first time in oocytes.